Neurons in the medial nucleus of the trapezoid body (MNTB) project glycinergic inhibition to multiple other auditory nuclei, which in turn send projections to additional auditory centers. Thus, the MNTB controls, directly or indirectly, the firing of a large number of auditory nuclei, and participates in computations as diverse as interaural intensity analysis, interaural time analysis, and a number of monaural tasks. Understanding these processes should require a detailed understanding of spike train transformations performed in the MNTB, and knowledge about functional circumstances, under which MNTB neurons may be silent and thus suspend their inhibitory control over the other auditory areas. However, one surprisingly large gap in our understanding of MNTB inhibits this level of understanding: MNTB principal neurons themselves receive substantial inhibitory inputs, which match the excitatory inputs in strength, and which are capable of suppressing activity in the MNTB. However, virtually nothing is known about these inhibitory inputs, their functional properties, the conditions under which they are activated, and how they interact with the excitatory inputs to shape MNTB activity. We propose to use a combined in-vivo and in-vitro electrophysiology approach to study the role of these inhibitory inputs. Our over-arching hypothesis is that inhibitory inputs to the MNTB shape the neuron's responses to complex and ongoing stimuli. Specifically, inhibition to MNTB may act as a mechanism to enhance temporal contrast, and sharpen responses to stimulus onset and transient components of complex sound activity. In aim 1 we propose to test in-vitro the hypothesis that specific inhibitory inputs suppress spiking in MNTB when certain sound stimuli are presented. We will determine the synaptic properties of the inhibitory inputs in response to simple and complex activity patterns, and test the interaction between excitation and inhibition during the processing of complex and ongoing stimulus patterns. In aim 2 we will focus, again with an in-vitro approach, on the role of glycine as a modulator of excitatory transmission that additionally sharpens onset responses of ongoing activity. We will test the hypothesis that glycine enhances excitatory transmission at the onset of stimulus trains, but depresses excitatory transmission during ongoing activity and thus acts to sharpen the onset response of MNTB neurons to complex and ongoing activity. In aim 3 we will investigate the role of GABAergic and glycinergic inputs to MNTB by using an in-vivo approach. We will test the hypothesis that inhibitory inputs to MNTB are tuned to best frequencies above the neuron's corresponding best excitatory frequency, and arrive at MNTB neurons with a slightly longer latency than the corresponding excitation. Thus, inhibitory inputs sharpen onset responses to sound stimuli in- vivo, and additionally suppress responses in MNTB neurons to frequency modulated components in sound stimuli, such as downward. All experiments will be performed in adult gerbils (p40 and older). In recent months we developed the techniques to successfully record from MNTB brain slices prepared from adult gerbils. We also developed the techniques to perform in-vivo recordings from age-matched animals, and perform pharmacological manipulations in-vivo by using multibarrel electrodes. Furthermore, we have a novel light-sensitive glutamate agonists at our disposal that allows for flashes of light to control brainstem neuronal firing. This method will be used to study the impact of fairly distant sources of inhibition to the MNTB. The proposed studies focus on understanding a nucleus that is the most important source for neural inhibition to the auditory brain stem, and the results will thus be significant for developing treatments for medical conditions resulting from unbalanced inhibition, such as tinnitus, audiogenic seizures, or presbycusis. PUBLIC HEALTH RELEVANCE: The medial nucleus of the trapezoid body (MNTB) is an auditory brain stem nucleus that controls information processing in many other auditory centers by sending inhibitory projections to these nuclei. However, there is a large gap in our understanding of the functioning of the MNTB: Its neurons themselves receive powerful inhibitory control from other brain areas, about which almost nothing is known. We propose to study these inhibitory inputs to MNTB and determine their functional role. The results from the research project will help our understanding of a number of pathological conditions and hearing impairments such as audiogenic seizures, tinnitus, or a decline in speech perception among the elderly.